CN1829922B - On-chip magnetic particle sensor with improved SNR - Google Patents

On-chip magnetic particle sensor with improved SNR Download PDF

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Publication number
CN1829922B
CN1829922B CN2004800221386A CN200480022138A CN1829922B CN 1829922 B CN1829922 B CN 1829922B CN 2004800221386 A CN2004800221386 A CN 2004800221386A CN 200480022138 A CN200480022138 A CN 200480022138A CN 1829922 B CN1829922 B CN 1829922B
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magnetic
magnetic field
sensor element
sensor
particle
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CN1829922A (en
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J·A·H·M·卡尔曼
M·W·J·普林斯
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Koninklijke Philips NV
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Koninklijke Philips Electronics NV
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01R—MEASURING ELECTRIC VARIABLES; MEASURING MAGNETIC VARIABLES
    • G01R33/00—Arrangements or instruments for measuring magnetic variables
    • G01R33/02—Measuring direction or magnitude of magnetic fields or magnetic flux
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01R—MEASURING ELECTRIC VARIABLES; MEASURING MAGNETIC VARIABLES
    • G01R33/00—Arrangements or instruments for measuring magnetic variables
    • G01R33/12—Measuring magnetic properties of articles or specimens of solids or fluids
    • G01R33/1269—Measuring magnetic properties of articles or specimens of solids or fluids of molecules labeled with magnetic beads
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N15/00—Investigating characteristics of particles; Investigating permeability, pore-volume, or surface-area of porous materials
    • G01N15/06—Investigating concentration of particle suspensions
    • G01N15/0656—Investigating concentration of particle suspensions using electric, e.g. electrostatic methods or magnetic methods
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N27/00—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means
    • G01N27/72—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating magnetic variables
    • G01N27/74—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating magnetic variables of fluids
    • G01N27/745—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating magnetic variables of fluids for detecting magnetic beads used in biochemical assays
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/543—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals
    • G01N33/54313—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals the carrier being characterised by its particulate form
    • G01N33/54326—Magnetic particles
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01R—MEASURING ELECTRIC VARIABLES; MEASURING MAGNETIC VARIABLES
    • G01R33/00—Arrangements or instruments for measuring magnetic variables
    • G01R33/12—Measuring magnetic properties of articles or specimens of solids or fluids
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N35/00—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor
    • G01N35/00029—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor provided with flat sample substrates, e.g. slides
    • G01N2035/00099—Characterised by type of test elements
    • G01N2035/00158—Elements containing microarrays, i.e. "biochip"
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N35/00—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor
    • G01N35/0098—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor involving analyte bound to insoluble magnetic carrier, e.g. using magnetic separation

Abstract

A device and method is disclosed for the detection or determination of the presence of magnetic particles (15), such as for example, but not limited to, magnetic tianoparticles. In particular it relates to an integrated or on-chip magnetic sensor element (11) for the detection of magnetic particles. The device and method of the present invention o er high signal-to-noise ratio and low power consumption and do not require an external magnetic field. They may be used for magnetic detection of binding of biological molecules on a micro-array or biochip.

Description

Has the on-chip magnetic particle sensor that improves signal to noise ratio (S/N ratio)
Technical field
The present invention relates to a kind of magnet sensor arrangement, it is used for determining the existence of at least one magnetic particle, and this magnet sensor arrangement comprises:
Suprabasil magnetic sensor element,
Be used for producing the magnetic field generator of AC magnetic field,
The sensor circuit that comprises magnetic sensor element, it is used for the magnetic of at least one magnetic particle of sensing, and the magnetic of this at least one magnetic particle is relevant with AC magnetic field.
This invention also relates to a kind of method of determining the existence of at least one magnetic particle, and the method includes the steps of:
Near magnetic sensor element, produce AC magnetic field,
Utilize the magnetic of at least one magnetic particle of magnetic sensor element sensing, the magnetic of this at least one magnetic particle is relevant with AC magnetic field.
The introducing of microarray or biochip is thoroughly changing for DNA (DNA (deoxyribonucleic acid)), RNA (RNA (ribonucleic acid)), protein, cell and cell fragment, the analysis of structural constituent samples such as (tissueelements).This application examples human gene type is in this way identified (genotyping) (for example, in hospital, perhaps by private doctor or nurse), biology screening (biological screening), biology and pharmaceutical research.
Biochip, be also referred to as biologic sensor chip, the biology microplate, genetic chip or DNA chip exist with their the simplest forms, i.e. a substrate, adhere to many different probe molecules thereon, the zone that defines on chip, if molecule to be analyzed or molecule fragment preferably mate, they can combine (bind) with it.For example, a dna molecular fragment is attached to unique complementary DNA (c-DNA) molecule fragment.The appearance of association reaction can be detected, for example by utilizing the fluorescent flag that is coupled with analyte molecules.This just provides a kind of ability, i.e. a small part of a large amount of different moleculars of parallel parsing or molecule fragment at short notice.A biochip can be chemically examined 10-1000 or more different molecular fragment.Can reckon with that as the achievement of the project of for example human genome project and the gene that comes one after another and protein function research, at 10 years of future, the practicality of information of utilizing biochip to obtain will increase sharply.
Background technology
G.Li etc. are at Jounal of Applied Physics, Vol93, number 10, pp7557-7559, " Detection of singlemicron-sized magnetic bead and magnetic nanoparticles usingspin valve sensors for biological applications " in 15 days Mays in 2003 described a series of Spin Valve (spin-valve) sensor, is used for detecting single super paramagnetic beads (superparamagnetic bead).Marked by magnetic bead is a biological molecule.
This sensor chip comprises a Wheatstone bridge, and this bridge arrangement is for having pair of sensors (Rsen) and reference tape (Rref) and two off chip resistors (R1 and R2) on chip.This sensor chip is arranged in the gap of two quadrature electromagnet, makes the y direction of rotary valve band (spin valve strips) aim at dc bias field Hb by a kind of like this mode, and this is laterally parallel with interchange feedback magnetic field Ht.
By being polarized in the magnetic microballon (microbead) on Spin Valve (spin valve) sensor with D.C. magnetic field, and utilizing the quadrature AC magnetic field to adjust its magnetization, people observe magnetic resistance (MR) signal that is caused to the magnetic couple plank field of rotary valve by the pearl of eliminating applied field from part and reduce.(lock-in) technology of locking can be used for measuring because MR reduces the voltage signal that causes.
When removing this pearl, can observe signal saltus step just above noise level, this shows the difference between original state (single pearl exists) and detected state (not having pearl).
The shortcoming of said system is that obtainable signal to noise ratio (S/N ratio) is limited.For example, the reference tape (Reference strip) that the sensor in the configuration of this Wheatstone bridge has a magnetoresistance material (Rref), it has introduced extra unnecessary noise.Because this high noise level, this system can not detect the signal of single pearl, only detects the difference of single pearl between existing or not existing.
Summary of the invention
An object of the present invention is to provide a kind of this kind of means of mentioning in the beginning paragraph, this device has improved signal to noise ratio (snr).
Can realize according to purpose of the present invention,, and be set on 100Hz or higher frequency, work because magnetic field generator is positioned in the substrate.
The noise level of magnet sensor arrangement is determined by several noise sources, (magnetic) 1/f noise that for example is present in magnetic sensor element self, electronic noise characteristic (for example, the noise of electronic sensing circuit (for example amplifier of Cai Yonging), skew, deviation) and unwanted magnetic field.The present invention is based on following knowing clearly, promptly under the low frequency state, for example is being lower than on the 100Hz frequency, and the 1/f noise of magnetic sensor element is preponderated.1/f noise causes by the fluctuation of the point-to-point of electric current, and reciprocal proportional with frequency.In magnetoresistive transducer, 1/f noise derives from the magnetic wave of free layer (free layer) moving.When the frequency of the AC magnetic field that generates is 100Hz or when higher, the dominant 1/f noise prior art (for example, Li adopts 40Hz) of comparing reduces significantly, and this produces improved signal to noise ratio (snr).
Advantageously when the frequency of AC magnetic field further is increased to a value, on this value, heat is white, and (Nyquist: Nyquist) noise level exceeds the 1/f noise level and becomes and preponderate.Making the present inventor feel pleasantly surprised is that result's proof is surpassing specific corner frequency f cIn the GMR sensor of ≈ 50kHz, hot white noise becomes preponderates.The white noise level has limited obtainable in theory detection limit.
To have high-frequency AC magnetic field in order generating, to use a conductor integrated in substrate, send alternating current by this conductor.The frequency of this alternating magnetic field can be far above the frequency of the prior art that adopts electromagnet.These electromagnets only can be operated in the low frequency of about 1-40Hz.Employing is such as electric wire, and another advantage of band etc. and so on conductor is that the prior art of comparing electromagnet needs relatively low power.Another advantage is that magnetic field generator mechanically aims at the magnetic sensed layer in clear and definite mode.This has just been avoided in measuring process the careful needs of aiming between electromagnet and sensor.
Magnetic field generator and sensing circuit can be integrated on the chip.This just allows very compact system.In addition, when having a plurality of magnetic sensor element, wherein these a plurality of magnetic sensor elements are used for having detected the magnetic particle of the label effect of biological molecule on sequence (array) or the biochip, in integrated all being connected than easier outside chip to sensor element and sensing circuit on the chip.Thin film technique allows multilayer metallization (multilevel metallization) scheme and compact integrated circuit (IC) design.
This substrate can comprise the electronic equipment of realizing all detections and control function (for example, the local measurement of temperature and pH).This has following advantage:
Its feasible big (optics) detection system that there is no need to adopt costliness,
It makes the surface density that further improves probe molecule (probed molecules) become possibility,
It has improved speed, accuracy and reliability,
It has reduced needed test volume amount, and
It has reduced labour cost.
When no matter (not only in hospital, and in private doctor's place) biochip provides absolute cheap method for diagnosis the place, and when their use caused the integral body cost decline of disease control, they may carry out large-scale production.
Magnetoresistive transducer based on GMR and TMR element can advantageously be used for measuring slow change procedure, for example in molecular diagnostics (MDx) field.Utilize magnetoresistance material can produce a rigidity, single element, the micro-structure detecting device, it can monitor tens simultaneously, hundreds of, several thousand or even millions of experiment.
In an advantageous embodiments, magnetic sensor element is positioned on the plane, and has a plurality of magnetic flux generators.
A plurality of magnetic field generators can be positioned at different layers with respect to the magnetic sensor element plane.
Another object of the present invention provides a kind of method at this type described in the beginning paragraph, and this method is used for detecting magnetic particle, has produced the signal to noise ratio (snr) that improves.
Can realize according to purpose of the present invention, because the frequency of AC magnetic field is chosen in 100Hz or higher.
Preferably, frequency is chosen as a value, is higher than the 1/f noise of magnetic sensor element at white (Nyquist) noise of the heat of this value magnetic sensor element.Noise level in detection system can be by the noise spectrum domination of magnetic sensor element.This magnetic sensor element can be GMR or TMR sensor.In these sensors based on magnetoresistance, 1/f noise is caused by the fluctuation of sensor free layer direction of magnetization.This free layer is the sensitive layer in GMR or TMR sensor.
When having a plurality of magnetic flux generator, this method can advantageously be used for determining the magnetic particles as the magnetic particle function of position, for example, and in the biological sample of a certain little sequence (micro-array) or biochip.
When a plurality of magnetic field generators with respect to the plane of magnetic sensor element be positioned at different layers (level) time, this method allows the surface concentration and the concentration by volume of difference and definite magnetic particle.In addition, this method is applicable to the position of determining magnetic particle on perpendicular to the direction on magnetic sensor element plane, and the position of determining to be parallel to the magnetic sensor element plane.
For accurate measurement, can use a kind of bearing calibration.The initial magnetic field that produces by (or a plurality of) magnetic field generator of under the situation that does not have magnetic particle, measuring.When carrying out measurement under the situation that has magnetic particle, from the actual measured value that obtains, deduct this measured value.
This correcting measuring value can be stored in the storer, and for example among the MRAM, it can be integrated on the chip with magnetic sensor element and testing circuit electronically.
Because do not need to apply the outer external magnetic field that produces of chip, noise level can further reduce, and therefore makes it possible to measure more accurately.Another advantage is the form factor (form factor) with the configuration of littler (biology) sensor interface.
In conjunction with the drawings with reference to hereinafter describing in detail, can be so that these and other characteristics of the present invention, feature and advantage be more obvious, and the form by example, principle of the present invention is described.This description only provides for example, does not limit the scope of the invention.The reference diagram of quoting below refers to accompanying drawing.
Description of drawings
Figure 1A shows the synoptic diagram of biosensor arrangement.
Figure 1B, 1C and 1D show the details of probe member, this probe member has the selectively binding site of combining target sample (binding site), and magnetic nano-particle (nanoparticle) direct or indirect in a different manner be attached to target sample.
Fig. 2 is according to the sectional view of the sensor device of first embodiment of the invention under the situation that does not have magnetic particle.
Fig. 3 is at the sectional view that exists under the situation of magnetic particle according to the sensor device of first embodiment of the invention.
Fig. 4 is the synoptic diagram according to the detection method of first embodiment of the invention.
Fig. 5 shows the magnetoresistive characteristic of GMR sensor element, AC magnetic field, and the GMR output signal that as a result of obtains.
Fig. 6 is as the magnetic moment figure that applies the magnetic nano-particle of magnetic field function.
Fig. 7 is the details of magnetization curve among Fig. 6.
Fig. 8 has schematically shown the dominant noise spectrum of GMR sensor element.
Fig. 9 is the sectional view of sensor device according to a second embodiment of the present invention.
Figure 10 is the sectional view according to the sensor device of third embodiment of the invention.
Figure 11 shows the combination as the Magnetic Sensor with two conductors that uses in fourth embodiment of the invention.
Figure 12 is the sectional view according to the sensor device of fourth embodiment of the invention.
Figure 13 is the synoptic diagram according to the detection method of the sensor device use of fourth embodiment of the invention.
Figure 14 is the sectional view of sensor described in the prior, and has shown the chip area size.
Figure 15 is the sectional view according to the sensor device of fourth embodiment of the invention, has shown the chip area size.
Figure 16 is the sectional view according to the sensor device of fifth embodiment of the invention.
Figure 17 is the sectional view according to the sensor device of sixth embodiment of the invention.
Figure 18 is the sectional view according to the sensor device of seventh embodiment of the invention.
In different figure, identical Reference numeral is represented identical or similar elements.
Embodiment
The present invention is described with corresponding certain embodiments and with reference to certain figures, but the present invention is not limited to this, and only limits the present invention by claim.The embodiment that describes only is schematically, is not restricted.In the accompanying drawings, some size of component may be amplified, and for the purpose of illustrating not be to draw in proportion.Wherein used term " to comprise " in instructions of the present invention and claim, it does not get rid of other element or step.Wherein when mentioning singular noun, used definite article or indefinite article, for example " a " or " an ", " the ", this comprises a plurality of these class nouns, unless mention especially.
The description of in Figure 1A, illustrating biosensor arrangement 50.It comprises case type shell (cartridge housing) 51, cavity 52 and/or be used for holding the raceway groove of material, analyte for example to be analyzed, and biochip 54.This biochip 54 is arranged on the set at the miniaturization test position (little sequence (micro-arrays)) on the solid substrate, and it allows to carry out at one time many tests, thereby obtains higher handling capacity and speed.It can be divided into tens of to thousands of small cavitys, its each comprise bioactive molecule, Duan DNA chain (strands) or probe for example.It can be three-dimensional, can move nearly 10,000 different chemical examinations at one time.Perhaps, chip 54 can manufacture more simply and have only 10 different chemical examinations operations at one time.Use (genetic decoding) except heredity, biochip 54 also is used in toxicology, in protein and the Biochemical Research, is used in clinical diagnosis and the scientific research, is used for improving disease detection, analyzes and final prevention.
Biochip 54 comprises a substrate, has at least one in its surface, preferred a plurality of probe area.Each probe area is included in its probe member 55 on part surface at least.This probe member 55 provides binding site 56, for example binding molecule or antibody, and selectively the combining target sample 57, for example target molecule species or antigen.Any bioactive molecule biologically that can be coupled on the matrix may be applied in this application.For example:
Nucleic acid: DNA, RNA two or strand or DNA-RNA mixing have or do not have distortion.Nucleotide sequence is known.
Protein or peptide have or do not have distortion, for example, and antibody, DNA or rna binding protein matter.Recently, announced the have yeast holoprotein group grid (grid) of (complete proteome ofyeast).
Oligosaccharides or polysaccharide or sugar,
Micromolecule, inhibitor for example, ligand so is cross connected to matrix or passes through spacer molecule.
Intersperse object on grid will be most likely composition family, peptide/protein family for example, oligonucleotides (oligonucleotides) family, inhibitor family (inhibitorlibraries).
Exist multiple different possibility that magnetic particle is connected to target sample, these examples are at Figure 1B, shown in 1C and the 1D.The dissimilar magnetic particle that can use in the present invention by people such as Urs Hafeli at " Scientific and Clinical Application ofMagnetic Carriers ", Plenum Press, New York, 1597, ISBN0-306-45687-7 describes to some extent.
In Figure 1B, by the sensor molecule 58 of magnetic particle 15 marks combining target sample 57 selectively.When carrying out random search, for example in the dna binding protein dna of the particular organization's extract that is attached to grid, to screen with gang's nucleotide, sensor molecule should have the feature of non-constant width.In this example, the sensor molecule that has the sept (spacer) of amino or carboxyl reaction can be of great use.Have sugar, other sensor molecule of DNA reactive group also is suitable.Under the situation of direct search, special sensor molecule can be used, and for example, the protein screening that wherein has anti-protein family is carried out for the protein-protein interaction of supposition, and antibody is a conspicuous selection.Unicellular and many cells antibody all can adopt.Shown in Figure 1B, magnetic particle 15 can be attached to target sample 57 indirectly.
In Fig. 1 C, target sample 57 molecules can be directly by magnetic particle 15 marks.
In Fig. 1 D, target sample 57 is by mark 60 marks.A kind of like this target sample that is labeled 57 (for example, (biotinylated) sample DNA of biotin (acyl) change) selectively is attached to binding site 56.By the sensor molecule 61 (for example, streptavidin) of magnetic particle 15 marks incorporation of markings 60 on target sample 57 selectively.In addition, magnetic particle 15 can be attached to target sample 57 indirectly.
The function of biochip 54 is as described below.Each probe member 55 has the binding site 56 of a particular type.Target sample 57 appears at or is delivered to probe member 55, and if binding site 56 and target sample 57 couplings, then they are bonded to each other.Magnetic particle 15 is coupled to target sample 57 directly or indirectly, as Figure 1B, shown in 1C and the 1D.Magnetic particle 15 allows to read the information of being collected by biochip 54.
The invention relates to and how to read the information of collecting by biochip 54 by magnet sensor arrangement.Below, the present invention will be with reference to the magnetoresistive devices as a magnet sensor arrangement part, AMR for example, and GMR or TMR device are described.Yet, the invention is not restricted to this, can also utilize any suitable magnetic sensor element, for example Hall sensor or SQUID (superconducting quantum interference device).
In first embodiment, device according to the present invention is a biology sensor, and will be referring to figs. 2 and 3 being described.This biology sensor detects at for example fluid, liquid, gas, viscoelastic medium, the magnetic particle in the samples such as gelinite or tissue sample.This magnetic particle may have very little size.Nano particle means that particle has the size of scope between 0.1nm and 1000nm at least, is preferably located between 3nm and the 500nm, more preferably between 10nm and 300nm.Magnetic particle can obtain the magnetic distance by the magnetic field that applies (for example, they can be paramagnetic) generation, and perhaps they can have permanent magnetic distance.Magnetic particle may be a kind of compound, for example is made up of one or more little magnetic particle inner at nonmagnetic substance or that be attached to it.As long as particle produces the non-zero response to the AC magnetic field frequency, just, when they produced magnetic susceptibility or magnetic permeability, they just can be used.
This device can comprise substrate 10 and circuit, for example integrated circuit.The surface measurements of device is represented by the dotted line among Fig. 2 and Fig. 3.In an embodiment of the present invention, term " substrate " can comprise any primer or the material that can adopt, and perhaps can form device, circuit or epitaxial loayer thereon.In another interchangeable embodiment, should " substrate " can comprise the semiconductor-based end, doped silicon for example, gallium arsenide (GaAs), gallium arsenide phosphatization thing (GaAsP), indium phosphide (InP), germanium (Ge), perhaps SiGe (SiGe) substrate.Should " substrate " exceptionally can also comprise insulation course except semiconductor-based bottom, for example, SiO 2Perhaps Si 3N 4Therefore, the term substrate also comprises glass, plastics, pottery, glass silicon (silicon-on-glass), silicon on sapphire (silicon-on sapphire) substrate.Therefore term " substrate " is used for defining widely the element of layer on the basis of layer that formation is concerned about or its part.Equally, " substrate " can be cambial thereon any other substrate, for example glass or metal level.To handle with reference to silicon hereinafter, because use silicon semiconductor usually, but those skilled in the art will be readily appreciated that the present invention and can also implement based on other semiconductor material systems, and those skilled in the art can select the substitute of suitable material as following insulating material and conductor material.
This circuit can comprise as the magnetoresistive transducer 11 of sensor element with the magnetic field generator of conductor 12 forms.Magnetoresistive transducer 11 can be the sensor of GMR or TMR type for example.Magnetoresistive transducer 11 can for example have prolongation, for example long fillet geometric configuration, but be not limited thereto geometric configuration.Sensor 11 and conductor 12 can orientate as (Fig. 2) close to each other one near in apart from g.Distance between sensor 11 and the conductor 12 can be for example between 1nm and the 1mm; 3 μ m for example.Minor increment is determined by IC technology.
In Fig. 2 and Fig. 3, introduce coordinate system and be used for representing, if sensor device is positioned on the xy plane, then sensor 11 mainly detects the x components in magnetic fields, promptly the x direction is the sensitive direction of sensor 11.The x direction of the arrow 13 expressions sensitivity of magnetoresistive transducer 11 among Fig. 2 and Fig. 3 according to the present invention.Because sensor 11 is responsive hardly on perpendicular to the direction (vertical direction among the figure or z direction) on sensor device plane, so the magnetic field 14 that is caused by the electric current that flows through conductor 12 can not be detected under the situation that does not have magnetic field nano particle 15 by sensor 11.By apply electric current to conductor 12 under the situation that does not have magnetic nano-particle 15, sensor 11 signals can be corrected.This correction is preferably carried out before any measurement.
In the time of near magnetic material (this may be, magnetic ion for example, molecule, nanoparticle 15, solid material or fluid with magnetic component) is positioned at conductor 12, it produces a magnetic apart from m, is marked by the field wire among Fig. 3 16.So magnetic produces bipolar stray field (dipolarstrayfield) apart from m, its position at sensor 11 has plane inner field component 17.Therefore, nano particle 15 deflects into magnetic field 14 the responsive x direction of the sensor of being represented by arrow 13 (Fig. 3) 11.The x component H in magnetic field xBe positioned at the responsive x direction of sensor 11,, and depend on the quantity N of magnetic nano-particle 15 by sensor 11 sensings NpAnd conductor current I c
The method that detects magnetic nano-particle according to an embodiment of the invention has been shown among Fig. 4.The modulation signal Mod (t) that comes from signal source 20 has suitable waveform, for example, and sinusoidal wave (sin at), and have high frequency such as but not limited to 50KHz, this modulation signal is sent to conductor 12 and modulates this conductor current I c" high frequency " according to the present invention means it is such frequency, and it can not be created on this frequency, and magnetic particle is sizable to be moved, the frequency of 100Hz or higher for example, and preferably 1KHz or higher more preferably is 50kHz or higher.
The modulated I that makes of conductor current c=I cSin at, and the electric current of this modulation causes magnetic field, and this mainly is vertical or the z direction in the position of magnetoresistive transducer 11 for this magnetic field, shown in Fig. 2 halfway line 14.
Current sensor I sFlow through magnetoresistive transducer 11.According near the existence of nano particle 15 magnetoresistive transducer 11, change in the magnetic field of sensor 11 positions, and therefore changed the resistance of sensor 11.
Fig. 5 has shown the magnetoresistive characteristic of GMR sensor.Under the situation that does not have magnetic particle, input signal is the AC magnetic field that comes from conductor.Existence according near nano particle 15 magnetoresistive transducer 11 changes in the magnetic field of sensor 11 positions, and has therefore changed the resistance of sensor 11.Magnetic field H in the responsive x direction of magnetoresistive transducer 11 xSingle order is proportional to the quantity N of magnetic nano-particle NpWith conductor current I c:
H x∝N npI c?sin?at
The different resistance of sensor 11 causes voltage drops different on sensor 11, and therefore causes the different measuring-signal by sensor 11 transmission.The response of AC magnetic field signal is shown schematically in the left-hand side of Fig. 5.The GMR output signal that as a result of obtains is a continuous wave.
The measuring-signal that is transmitted by magnetoresistive transducer 11 sends amplifier 21 to, thereby is used for amplifying generation amplifying signal Ampl (t).
This amplifying signal Ampl (t) is detected, and carries out demodulation by demodulation multiplier 22 simultaneously, and wherein this signal and modulation signal Mod (t) (equaling sin in this case) multiply each other, and produces M signal Mult (t), and this M signal Mult (t) equals:
Mult(t)＝N npI c?sin 2?at＝N npI c1/2(1-cos2at)
In the end a step, this M signal Mult (t) sends by low-pass filter 23.Signal Det (t) that the result obtains and the quantity N that is present in the magnetic nano-particle 15 on sensor 11 surfaces NpBe directly proportional.
In addition, amplifier 21 can pass through the low frequency rejector, capacitor C for example, and AC is coupled to magnetoresistive transducer 11.Capacitor has further strengthened the low frequency inhibition.
In the present invention, magnetic particle, for example magnetic nano-particle 15, are operated in the range of linearity 24, this means that the magnetic of magnetic particle 15 is followed magnetic field intensity (Fig. 6) linearly apart from m.This means that also the very little magnetic field of needs only causes the magnetic distance of nano particle 15.For example, for the nano particle with diameter 50nm, magnetic relatively can be from-0.015Am apart from the full linear scope 24 of m and magnetic field 2/ g is to+0.015Am 2/ g, magnetic field intensity that need be from-10kA/m to+10kA/m.Be operated at magnetic nano-particle 15 under the situation of zone of saturation 25, need higher magnetic field, just, 80kA/m at least.From Fig. 6, can calculate and equal m at the loss of signal ratio of linear zone and saturation region operation Lin/ m Sat=0.015/0.025=0.6.
In the embodiment that is proposed, magnetic is apart from being produced by the magnetic field with low field intensity degree, this magnetic field and then again by magnetic field generator, and for example the electric current that flows in conductor 12 produces.If sensor 11 has one and elongates in a special example, promptly long fillet geometric configuration, and the distance between conductor 12 and the sensor 11 is g=3 μ m, has amplitude I cThe conductor current of=20mA, perpendicualr field intensity equals H z=I/2.w ≈ 1kA/m.The magnetization that detailed magnetization curve map is illustrated in 1kA/m among Fig. 6 equals 0.0015Am 2/ g (Fig. 7).As for saturated situation, detected signal reduces with factor 0.0015/0.025=0.06.
By using detection method, can reduce noise as describing among Fig. 4.This will describe in following discussion.
Fig. 8 schematically shows the overriding noise source of the detection system of Fig. 4.At the low frequency of AC magnetic field, the 1/f noise of GMR sensor element has surpassed all other electronic noise source.
In this detection is under the 1/f noise condition of limited, and this is a situation in this embodiment, and the SNR loss can be by being increased to f with modulating frequency from for example 10Hz Mod=(1/0.06 2) .10=2.8kHz compensates.By with modulating frequency f ModBe increased to the dominant point of thermonoise, be generally 50kHz, can further improve SNR.This will cause the method (50/2.8) with respect to discussion in WO 03054523 1/2The clean improvement of=4=12dB.By the lower limit of step-down amplifier thermonoise, it is apparent that increases modulating frequency f ModSurpass 50kHz, thereby SNR will improve further.
After signal to noise ratio (S/N ratio) was improved, another advantage of the detection method of Miao Shuing was the external magnetic field that comes from outside the chip needn't be provided in this embodiment.Send modulation signal by conductor 12 and produce magnetic field.
In addition, the magnetic particle of employing needn't be very big; They can have little magnetic distance, because do not need moving of magnetic particle for detecting.And during magnetic field applies or between its relaxation period, can both carry out detection, therefore needn't provide to have the long enough macroparticle of slack time.
Another advantage of this embodiment do not need to be (biology) chemical constitution of this sensor.Should can comprise by (biology) chemical constitution:
(1) picture on surface forms.This refers to the composition on surface, wherein this pattern in some way with substrate on or other structure in the substrate aim at.This pattern can comprise the molecule of individual layer, membraneous material, perhaps even the material of having removed.
(2) surface modification.This refers to surface (biology) chemical modification, for example specific capture molecule is coupled to the surface.Surface modification can apply with mode of composition, for example with respect in suprabasil sensor alignment.
Traditional particle sensor when being applied to biology sensor, providing the surface structure of some types so that target molecule can be attached to their surface usually, thereby has determined the concentration of target molecule in solution to be analyzed.Under situation of the present invention, this surface structure no longer is necessary, and is perhaps simpler, because applied very uneven magnetic field, part.Even, still can detect signal when this surface coverage has equally distributed magnetic particle.
Another advantage is the several measurements of possible executed in parallel, rather than order is carried out.This magnetic field owing to each conductor is concentration of local, so can utilize different magnetic field (frequency, amplitude etc.) at difference.
In a second embodiment, the geometric configuration to different devices has applied the detection method of describing in any one previous embodiment.The device geometric configuration of Miao Shuing schematically illustrates in Fig. 9 in this embodiment.This conductor 12 is between substrate 10 and magnetoresistive transducer 11.In this case,, need under the situation that does not have magnetic particle 15, carry out correcting measuring in advance, the magnetic field that the magnetic field generator 11 on this correcting measuring measured chip produces in order to measure.After this utilize the correcting measuring value of this acquisition, and will under the situation that has magnetic particle 15, carry out the actual measured value that obtains when measuring and deduct this correcting measuring value.
In the 3rd embodiment, shown in Figure 10, conductor 12 is integrated in the magnetoresistive transducer 11, therefore forms one integrated sensor/conductor means 32.This integrated sensor/conductor means 32 had not only produced but also had detected magnetic field.Yet because the electric weight in high resistance sensor 32 dissipates, the sensor current that allows is less than the conductor current I that allows in embodiment before now cHere, also need in advance correcting measuring.
By understanding, can improve the accuracy of (biology) sensor about the concentration of magnetic particle information as function of position.By utilizing basis method of the present invention as mentioned above, only can determine the quantity of magnetic particle 15.
In the 4th embodiment, a kind of apparatus and method have been described, be used for determining the function of the concentration (for example, nano-beads (beads)) of magnetic material as the position of the sensor 11 of comparing.
Device according to this embodiment can comprise the integrated circuit with magnetic sensor element 11, this magnetic sensor element can be a magnetoresistive sensor element for example, for example GMR or TMR sensor element, and two conductor 12a-b, each is in a side of sensor element 11.In Figure 11 and 12, show device with skeleton view and cut-open view form respectively according to this embodiment.
Figure 12 shows the sectional view according to this embodiment device.If this sensor device is positioned on the xy plane, this sensor 11 only detects the magnetic-field component at specific direction, the x component in magnetic field for example, and just, the x direction is the sensitive direction of sensor 11.This sensitive direction is illustrated by arrow 13.Therefore, when by the electric current I that flows through conductor 12a and 12b respectively 1And I 2When the magnetic field 14a that causes, 14b are positioned at the z direction of sensor 11 positions, can not detect magnetic field 14a, 14b at the situation lower sensor 11 that does not have magnetic particle 15.
At magnetic particle, for example nano particle 15, when being present on the surface of sensor 11, they each produce a magnetic apart from m, by the field wire 16a among Figure 12,16b represents.This magnetic is apart from producing the bipolar stray field, and its position at sensor 11 has plane inner field component 17a, 17b.
The z component H in magnetic field zRoughly be directly proportional with 1/x, perhaps therefore and being inversely proportional between magnetic particle 15 and the conductor apart from x.Therefore, the position at the magnetic particle 15 of xy plane privileged site is depended in the sensitivity of testing agency.More specifically, 15 pairs of magnetic particles are in each conductor 12a, the electric current I among the 12b 1And I 2Response depend on the x position of magnetic particle 15 in the xy plane, it can be found out from the curve map of Figure 12 lower part.In this curve map, described in response to conductor current I 1And I 2, field strength H in the plane that produces by magnetic particle 15 at xy planimetric position x X, 1And H X, 2
By utilizing the time, frequency, perhaps phase place (quadrature (quadra ture)) multiplexing technique measurement H X, 1And H X, 2, can derive the x position of magnetic particle 15.
(12a 12b) and when increasing between the sensor element (11), will become more vertical with respect to the magnetic field on magnetic sensor element (11) surface at conductor when this distance.It is more vertical to this means that magnetic nano-particle will be magnetized.This has caused reducing the output response of GMR sensor.Detection sensitivity therefore can than 1/x reduce rapider, as mentioned above.
Within the scope of the invention, the present invention includes the sensor of measurement more than a magnetic beads (bead) 15.Under the situation that has a plurality of magnetic particles 15, the integration of these sensor 11 measurements on magnetic particles is as the function of the x position of sensor 11.
According to an embodiment, by the definite magnetic particles of frequency multiplex method as the x function of position.It is shown in Figure 13.The first modulation signal Mod 1(t) send to the first conductor 12a from the first signal source 20a and come modulating current I 1, and send to the first demodulation multiplier 22a.This modulating current I 1Flow through conductor 12a, produce magnetic field, shown in Figure 12 halfway line 14, it is oriented orthogonal to the plane of sensor element 11 substantially in the position of sensor 11.In the time of near magnetic particle 15 is positioned at sensor 11, changed, and therefore changed the resistance of sensor 11 in the magnetic field of sensor 11 positions.The change of resistance causes voltage drops different on sensor 11, and therefore causes the different measuring signal that is transmitted by resistance 11.Measuring-signal sends by amplifier 21, and the measuring-signal Ampl (t) that amplifies is by the first modulation signal Mod 1(t) demodulation.The first M signal Mult that this obtains 1(t) send the formation first detection signal Det by the first low-pass filter 23a 1(t).
Electric current I in the second conductor 12b 2By the second modulation signal Mod 2(t) modulation.Second modulation signal sends among the second demodulation multiplier 22b, and wherein it utilizes measuring-signal Amp l (t) demodulation of amplifying, thereby forms the second M signal Mult 2(t).The second M signal Mult 2(t) send by the second low-pass filter 23b, thereby form the second detection signal Det 2(t).
The first and second detection signal Det 1(t) and Det 2(t) all be applied to interpreting means 34.This first and second detection signal Det 1(t) and Det 2(t) be I 1And I 2The measuring of magnetic particles in the coverage respectively.By explaining this two detection signal Det 1(t) and Det 2(t), the information about magnetic particle 15 CONCENTRATION DISTRIBUTION can obtain.
Normalization difference signal PosX is provided by following formula:
PosX = Det 1 ( t ) - Det 2 ( t ) Det 1 ( t ) + Det 2 ( t )
And representing the average x position of magnetic particle 15.
With signal SUM=Det 1(t)+Det 2(t) be a kind of tolerance, this tolerance is the sum about magnetic particle 15, their magnetization (diameter, magnetic permeability) and on perpendicular to the direction on sensor element 11 planes their position, be their position z under present case.
This ratio:
R = Det 1 ( t ) Det 2 ( t )
Can also be used as the sensitive direction of magnetic particle 15 about sensor element 11, be the indication of the position of x direction in this case.
Under the identical situation of the frequency of Mod1 and Mod2, magnetic field is zero in the middle of sensor.By changing the amplitude balance of two electric currents, can drift about zero point along the x axle.In this way, can collect other information about distribution of particles.
Above an advantage of the device described among the 4th embodiment be, the prior art of comparing, the entire chip area can be used for measuring.As its result, with respect to device of the prior art, this chip area is reduced.Figure 14 illustrates sectional view according to the part of the sensor device of prior art WO03054523.This figure has only represented half of complete in the prior art Wheatstone bridge (Wheatstone bridge) configuration.This sensor element 35 is positioned with for example 3 μ m adjacent at interval.On the opposite limit of approaching sensor element 35, stayed the space of 1.5 μ m.From the above, clearly finding out in order to carry out single test needs 2*12 μ m=24 μ m bar wide by 36.Bio-sensing area 37, just Zhuan Zhi working area is 6 μ m, as shown in figure 14.
At the 4th embodiment of the invention described above (Figure 12), utilize device (Figure 15) to obtain bio-sensing chip 37 with 6 μ m (Figure 15) bars wide 36.One sensor element 11 is between two conductor 12a and 12b.If for example this sensor element 11 has as 3 μ m width in existing apparatus, and sensor 11 edges and conductor 12a, the distance in the middle of the 12b is 1.5 μ m, and the complete strips that can obtain 6 μ m is wide.With respect to prior art, chip area can reduce with the factor 4, promptly doubles 12 μ m than 6 μ m.
In the fifth embodiment of the present invention, an improvement sensor device with respect to front embodiment has been described.In order between the surface of magnetic particle 15 and overall density, to distinguish, need be perpendicular to the resolution on sensor element 11 in-planes, it is corresponding to the z direction of the coordinate system of introducing among Figure 16.As shown in figure 16, compare magnetic field 14a and the 14b of conductor 12a and 12b of conductor 12c and 12d produces magnetic field 14c and 14d respectively.By the combination from four conductor 12a, 12b, the sensor signal that 12c, 12d send can obtain the information about magnetic particle 15 concentration on x and z direction.
This z resolution can further improve, and this need be by use more conductor on perpendicular to the direction on sensor element 11 planes, as the vertical direction or the z direction of expression.This is presented among the 6th embodiment among Figure 17. Conductor 12a and 12b are positioned at the both sides of closing on magnetic sensor 11, on perpendicular to the same horizontal plane on the direction on sensor element 11 planes (level). Conductor 12c, 12d, 12e and 12f between substrate 10 and sensor 11, conductor 12c and 12d with respect to conductor 12e and 12f in different z position.And the combination of the sensor signal that produces from different conductor 12a to 12f can provide the information about magnetic particle 15 integral body and surface concentration.
In another the 7th embodiment, the electric current in conductor 12c and 12d has reverse direction as shown in figure 18, and this conductor is positioned at the surface level between substrate 10 and the magnetic sensor 11.In this way, conductor 12c and 12d may produce a strong magnetic field gradient in the x direction.This embodiment is favourable for strengthening spatial resolution.
In embodiment 4 to 7, suppose that the position of magnetic particle 15 can not change during the field scan that relates to this magnetic particle 15 is measured.Can make such hypothesis, be because of weak magnetic force that is applied by the electric current among the conductor 12a-12f and slowly diffusion.
In the unlimited volume of room temperature water solution, diameter for example is that the diffusion constant of the single magnetic pearl (bead) of 100nm equals according to the Stokes-Einstein equation:
D = kT 6 πηR = 1.38 · 10 - 23 · 300 6 π · 10 - 3 · 50 · 10 - 9 = 4.4 · 10 - 12 m 2 / s
From equation, can obtain to have the coefficient of diffusion of low value.When for example applying 10MHz wobble frequency (wobble frequency), the propagation distance of magnetic particle 15 equals in one direction during 1 rolling period (wobble period):
L = 2 Dt = 2 · 4.4 · 10 - 12 · 10 - 7 = ln m
Suppose each now 100 rolling periods of measuring, the displacement of 100nm nano particle 15 equals 10nm.
The magnetic force that is applied on the magnetic particle 15 by magnetic field can be compressed into universal equation:
F = ▿ ( mB ) ≈ m ▿ B = m ∂ B ∂ w = m ∂ ( μ 0 I 2 πw ) ∂ w = - m μ 0 I 2 πw 2
If for example consider 50nm pearl 15, and by the electric current (I in the conductor 12 c=the magnetic that 20mA) produces is apart from m ≈ 6.10 -14Am 2, then for the sensor with the wide w=3 μ of GMR bar m, polarity equals:
F = 6 · 10 - 18 · 4 π · 10 - 7 · 0.02 2 π · ( 3 · 10 - 6 ) 2 = 2.7 fN
Because the effect of external force F, the speed of single particle 15 equals in aqueous solution:
v = F 6 πηR = 2.7 · 10 - 15 6 π · 10 - 3 · 50 · 10 - 9 = 2.9 μm / s
During 100 rolling periods, under the situation of particle 15 by the field excitation of single conductor 12, this displacement equals:
x = v · 100 f = 2.9 · 10 - 6 · 100 10 7 = 30 pm
Therefore, the term of execution measuring, can ignore this displacement.Have several advantages with respect to prior art by the apparatus and method that a plurality of embodiment of the present invention describe.At first, this method has little shape factor.This means:
(1) between magnetic field that produces and sensor element, there not be the problem of aligning, and
(2) only a little volume need be magnetized, and this means to have low power consumption.
This biology sensor itself and surface circuit may very little and low-power, and this is because owing to do not need the external magnetic field, so there is not coil.
Another advantage is because integrated sensor produces low-power consumption.Device of the present invention has the power consumption of 10mW, has the 8W power consumption in order to drive under the situation that for example there is external coil in magnetic devices in the prior art of comparing.In addition, owing to remove 1/f noise and the inhibition of LF magnetic field, can obtain higher SNR.Another advantage is that detection method makes and may utilizes sensor device that it is owing to apply the surface structure that local magnetic field does not need the sensor device surface.Yet, can the application surface composition, and can bring extra benefit, for example there is not non-essential loss away from the target molecule of sensor.
In addition, can obtain littler chip area because chip area 100% can be used as bio-sensing zone or perform region.Utilize the method according to this invention, can distinguish between the surface of magnetic particle 15 and overall density, this is because in the spatial resolution of x and z direction.Although it should be understood that for device according to the present invention preferred embodiment here has been discussed, ad hoc structure and configuration and material without departing from the scope and spirit of the present invention, can carry out various changes and revision in form and details.
For example, the present invention is not limited to single magnetoresistive transducer 11, and can also be applied to the situation that the magnetic particle in multisequencing (multi-array) biology sensor detects.Under the sort of situation, sensor element 11 on every side can be realized the function of conductor 12.This is favourable, because do not need one (or a plurality of) extra conductor 12 in the multisequencing biochip.

Claims (16)

1. magnet sensor arrangement that is used for determining the existence of at least one magnetic particle, this magnet sensor arrangement comprises:
Suprabasil magnetic sensor element,
Magnetic field generator is used to produce AC magnetic field,
Sensor circuit comprises magnetic sensor element, is used for the magnetic characteristic of at least one magnetic particle of sensing, and wherein said magnetic characteristic is relevant with this AC magnetic field,
It is characterized in that:
This magnetic field generator is integrated in this substrate, and is arranged to and is operated on 100Hz or the higher frequency, and wherein on described frequency, the hot white noise of this magnetic sensor element surpasses the 1/f noise of this magnetic sensor element and preponderates.
2. magnet sensor arrangement as claimed in claim 1, it is characterized in that, this sensor circuit comprises the amplifier that is connected to this magnetic sensor element, and this magnetic field generator is arranged to and is operated on such frequency, surpasses the 1/f noise in the output of this amplifier and preponderates at the hot white noise in the output at this amplifier on this frequency.
3. magnet sensor arrangement as claimed in claim 1, wherein this magnetic field generator comprises conductor and the ac current source that is used for producing the alternating current that flows through this conductor.
4. magnet sensor arrangement as claimed in claim 3, wherein the direction of this AC magnetic field in the immediate area of this magnetic sensor element perpendicular to the plane of this magnetic sensor element.
5. as the described magnet sensor arrangement of any one claim among the claim 1-4, wherein this magnetic field generator and this sensor circuit form integrated circuit.
6. as the described magnet sensor arrangement of any one claim among the claim 1-4, wherein said magnetic field generator and described magnetic sensor element location adjacent one another are in substrate.
7. as the described magnet sensor arrangement of any one claim among the claim 1-4, wherein said magnetic field generator is positioned between described substrate and the described magnetic sensor element.
8. as the described magnet sensor arrangement of any one claim among the claim 1-4, this magnetic sensor element is arranged in the plane, wherein said magnetic field generator is located in a side of contiguous this magnetic sensor element, and with respect to the direction vertical with the plane of this magnetic sensor element, another magnetic field generator of location on same position corresponding on the relative side of this magnetic sensor element.
9. as the described magnet sensor arrangement of any one claim among the claim 1-4, wherein said magnetic sensor element is a magnetoresistive sensor element.
10. as the described magnet sensor arrangement of any one claim among the claim 1-4, also comprise the device of the concentration that is used for definite magnetic particle.
11. magnet sensor arrangement as claimed in claim 10, the device that wherein is used for the concentration of definite magnetic particle comprises a plurality of magnetic field generators.
12. magnet sensor arrangement as claimed in claim 11, this magnetic sensor element is arranged in the plane, and wherein a plurality of magnetic field generators are with respect to the plane of this magnetic sensor element and be positioned on the different surface levels.
13. as the described magnet sensor arrangement of any one claim among the claim 1-4, wherein at least one magnetic particle is the magnetic label that is coupled to biomolecule.
14. one kind is used to utilize magnet sensor arrangement as claimed in claim 8 to determine the method for the concentration of magnetic particle according to the position of magnetic particle, wherein each magnetic field generator produces the AC magnetic field with different modulating frequency, the output signal of magnetic sensor element is by demodulation, thereby produce signal, from described signal with different frequency, determine the quantity and the position of magnetic particle with different frequency.
15. one kind is used to utilize magnet sensor arrangement as claimed in claim 12 to determine the surface concentration of magnetic particle and the method for total concentration, wherein a plurality of magnetic field generators produce the AC magnetic field component in the direction perpendicular to the plane at magnetic sensor element place, determine the position of magnetic particle from described magnetic-field component.
16. method as claimed in claim 15, wherein each magnetic field generator produces the AC magnetic field with different modulating frequency, the output signal of this magnetic sensor element is by demodulation, thereby produce signal, from described signal with different frequency, determine the quantity and the position of magnetic particle with different frequency.
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104969085A (en) * 2012-07-13 2015-10-07 蒙彼利埃大学 Micromagnetometry detection system and method for detecting magnetic signatures of magnetic materials.

Families Citing this family (84)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8623668B2 (en) 2004-11-05 2014-01-07 Imec Method for transport of magnetic particles and devices therefor
EP1919619A2 (en) 2005-07-21 2008-05-14 Koninklijke Philips Electronics N.V. Sensor chip for a biosensor
JP2009508103A (en) 2005-09-08 2009-02-26 コーニンクレッカ フィリップス エレクトロニクス エヌ ヴィ Micro sensor device
WO2007034358A2 (en) 2005-09-22 2007-03-29 Koninklijke Philips Electronics N. V. Sensor device with generator and sensor current sources
US20080246470A1 (en) 2005-10-12 2008-10-09 Koninklijke Philips Electronics, N.V. Magnetic Sensor Device With Field Compensation
US20080246471A1 (en) * 2005-10-12 2008-10-09 Koninklijke Philips Electronics, N.V. Magnetic Sensor Device With Different Internal Operating Frequencies
US20080238411A1 (en) * 2005-10-19 2008-10-02 Koninklijke Philips Electronics, N.V. Magneto-Resistive Nano-Particle Sensor
WO2007060568A2 (en) * 2005-11-23 2007-05-31 Koninklijke Philips Electronics N. V. Magnetic sensor device with sample chamber
US20080314749A1 (en) 2006-01-04 2008-12-25 Koninklijke Philips Electronics N.V. Microelectronic Device with Magnetic Excitation Wires
CN101379384A (en) * 2006-02-03 2009-03-04 皇家飞利浦电子股份有限公司 Magnetic sensor device with reference unit
WO2007105141A2 (en) * 2006-03-15 2007-09-20 Koninklijke Philips Electronics N. V. Magnetic sensor device with gain stabilization
WO2007105143A2 (en) * 2006-03-15 2007-09-20 Koninklijke Philips Electronics N. V. Sensor device with alternating excitation fields
EP1999272B1 (en) 2006-03-21 2017-11-01 Koninklijke Philips N.V. Microelectronic sensor device with sensor array
WO2007113724A2 (en) * 2006-03-30 2007-10-11 Koninklijke Philips Electronics N.V. Magnetoresistive sensor as temperature sensor
JP5188091B2 (en) * 2006-03-31 2013-04-24 キヤノン株式会社 Sensor element, magnetic particle detection method using the element, and target substance detection method
WO2007122542A2 (en) * 2006-04-26 2007-11-01 Koninklijke Philips Electronics N. V. Calibration of a magnetic sensor device
US20090102472A1 (en) * 2006-05-09 2009-04-23 Koninklijke Philips Electronics N.V. Magnetic sensor device with field generators and sensors
WO2007132374A1 (en) * 2006-05-09 2007-11-22 Koninklijke Philips Electronics N. V. A magnetic sensor device for and a method of sensing magnetic particles
US20090219012A1 (en) 2006-05-09 2009-09-03 Koninklijke Philips Electronics N.V. Microelectronic sensor device for concentration measurements
CN101438142B (en) 2006-05-10 2013-10-30 皇家飞利浦电子股份有限公司 Rapid magnetic biosensor
CN101443674A (en) * 2006-05-10 2009-05-27 皇家飞利浦电子股份有限公司 System and methods for actuation on magnetoresistive sensors
JP2009543038A (en) 2006-06-28 2009-12-03 コーニンクレッカ フィリップス エレクトロニクス エヌ ヴィ Magnetic sensor device and method for detecting magnetic particles
EP2038670B1 (en) * 2006-06-28 2010-11-17 Koninklijke Philips Electronics N.V. Magnetic sensor device with field generators and sensor elements
JP2009544033A (en) * 2006-07-17 2009-12-10 コーニンクレッカ フィリップス エレクトロニクス エヌ ヴィ Attraction and separation of magnetic or magnetizable objects from the sensor surface
DE102006051482A1 (en) * 2006-07-31 2008-02-14 Nikolaus Bartels Arrangement for detecting substances, manufacturing the arrangement and its use
EP2052245A2 (en) * 2006-08-09 2009-04-29 Koninklijke Philips Electronics N.V. Magnetic sensor device on a microchip
EP2054725A2 (en) * 2006-08-15 2009-05-06 Koninklijke Philips Electronics N.V. Magnetic sensor device
SG145747A1 (en) * 2006-09-15 2008-09-29 Nanyang Polytechnic Packages of apparatus for non-invasive detection of pulse rate and blood flow anomalies
US20090314066A1 (en) 2006-09-20 2009-12-24 Koninklijke Philips Electronics N.V. Sensor device for and a method of sensing particles
CN101523214A (en) 2006-10-09 2009-09-02 皇家飞利浦电子股份有限公司 Magnetic sensor device with pairs of detection units
RU2487338C2 (en) 2006-12-12 2013-07-10 Конинклейке Филипс Электроникс Н.В. Microelectronic sensor device for detecting label particles
WO2008072183A1 (en) 2006-12-15 2008-06-19 Koninklijke Philips Electronics N.V. Sensor device comprising means for determining the sample covered area of the sensitive surface
EP2095121A2 (en) 2006-12-18 2009-09-02 Koninklijke Philips Electronics N.V. Magnetic sensor device with suppression of spurious signal components
EP2095122A2 (en) * 2006-12-18 2009-09-02 Koninklijke Philips Electronics N.V. Magnetic sensor device with robust signal processing
RU2460058C2 (en) * 2006-12-19 2012-08-27 Конинклейке Филипс Электроникс Н.В. Measuring agglutination parameters
EP1936350A1 (en) * 2006-12-19 2008-06-25 Koninklijke Philips Electronics N.V. A method for quantitatively measuring agglutination parameters
EP2104865B1 (en) 2007-01-12 2010-06-23 Koninklijke Philips Electronics N.V. A sensor device for and a method of sensing magnetic particles
CN101611316A (en) 2007-02-01 2009-12-23 皇家飞利浦电子股份有限公司 The magnetic sensor device of sensing magnetic particles and method
WO2008102218A1 (en) 2007-02-23 2008-08-28 Koninklijke Philips Electronics N.V. A sensor device for and a method of sensing magnetic particles
US20100182002A1 (en) 2007-02-23 2010-07-22 Koninklijke Philips Electronics N.V. Magnetic sensor device with field generator and sensor element
US8927260B2 (en) * 2007-03-12 2015-01-06 Fabrico Technology, Inc. Anaylte detection system using an oscillating magnetic field
WO2008120169A1 (en) * 2007-04-03 2008-10-09 Koninklijke Philips Electronics N. V. Sensor device with magnetic washing means
CN101754811A (en) 2007-07-09 2010-06-23 皇家飞利浦电子股份有限公司 Microelectronic sensor device with magnetic field generator and carrier
FR2920875B1 (en) * 2007-09-07 2009-12-04 Magnisense Tech Limited METHOD AND DEVICE FOR ANALYZING MAGNETIC MATERIAL, APPARATUS INCLUDING THE DEVICE
EP2220478A2 (en) * 2007-09-24 2010-08-25 Koninklijke Philips Electronics N.V. Microelectronic sensor device with an array of detection cells
EP2208045B9 (en) 2007-10-25 2012-01-04 Koninklijke Philips Electronics N.V. Sensor device for target particles in a sample
US8339608B2 (en) 2007-11-05 2012-12-25 Koninklijke Philips Electronics N.V. Method for detecting redispersion of beads
KR20100115744A (en) 2008-01-17 2010-10-28 더 리전츠 오브 더 유니버시티 오브 캘리포니아 Integrated magnetic field generation and detection platform
EP2245462B1 (en) 2008-01-22 2017-05-31 Koninklijke Philips N.V. Detection of target components with the help of indicator particles
JP5628784B2 (en) 2008-03-17 2014-11-19 コーニンクレッカ フィリップス エヌ ヴェ Cartridge for assay with magnetic particles
DE102008000943B4 (en) * 2008-04-02 2015-02-19 Zf Friedrichshafen Ag Diagnostic Hall sensor and method for functional diagnosis of a Hall sensor device
JP5469660B2 (en) * 2008-05-14 2014-04-16 コーニンクレッカ フィリップス エヌ ヴェ Oxygen concentration measurement by GMR
EP2338052B1 (en) 2008-10-16 2019-11-20 Koninklijke Philips N.V. Method and device for determining the amount of magnetically labeled target components
BRPI0914098A2 (en) * 2008-10-16 2015-11-17 Koninkl Philips Electronics Nv biosensor
RU2520607C2 (en) 2008-10-17 2014-06-27 Конинклейке Филипс Электроникс Н.В. Actuation with pulsed magnetic field for sensitive analysis
US9720003B2 (en) 2008-12-22 2017-08-01 Koninklijke Philips Electronics N.V. Assay for Troponin I using magnetic labels
CN101625402B (en) * 2009-07-31 2012-07-18 华东师范大学 Method for improving nuclear magnetic resonance signal to noise ratio
CN102985823B (en) 2010-07-05 2015-09-30 皇家飞利浦电子股份有限公司 With the check system that sample is cultivated
WO2012014018A1 (en) 2010-07-30 2012-02-02 Poly Medicure Limited Catheter introducer
DE102010040391B4 (en) * 2010-09-08 2015-11-19 Siemens Aktiengesellschaft Magnetic flow cytometry for single cell detection
US9207210B2 (en) 2010-09-09 2015-12-08 Koninklijke Philips N.V. Method and a device for attracting magnetic particles to a surface
US8941966B2 (en) 2010-09-17 2015-01-27 Koninklijke Philips N.V. Magnetic system for particle attraction in a plurality of chambers
WO2012069988A1 (en) 2010-11-25 2012-05-31 Koninklijke Philips Electronics N.V. Cartridge for examinations of a sample
US9841421B2 (en) 2010-11-30 2017-12-12 Koninklijke Philips N.V. Sensor device for magnetically actuated particles
US9304130B2 (en) * 2010-12-16 2016-04-05 International Business Machines Corporation Trenched sample assembly for detection of analytes with electromagnetic read-write heads
CN102141540B (en) * 2010-12-31 2012-07-25 中国科学院物理研究所 Device and method for measuring AC susceptibility of nano magnetic liquid
EP2527814A1 (en) 2011-04-27 2012-11-28 Koninklijke Philips Electronics N.V. Sensor system with an exchangeable cartridge and a reader
JP2014521060A (en) 2011-06-28 2014-08-25 コーニンクレッカ フィリップス エヌ ヴェ Means for testing body fluids
EP2559488A1 (en) 2011-08-18 2013-02-20 Koninklijke Philips Electronics N.V. Control of fluid flow in a microfluidic system
US9927431B2 (en) 2011-09-14 2018-03-27 Regents Of The University Of Minnesota External field—free magnetic biosensor
EP2768769A1 (en) 2011-10-19 2014-08-27 Regents of the University of Minnesota Magnetic biomedical sensors and sensing system for high-throughput biomolecule testing
WO2013102850A1 (en) * 2012-01-04 2013-07-11 Insituto De Engenharia De Sistemas E Computadores Para Os Microsistemas E As Nanotecnologias Monolithic device combining cmos with magnetoresistive sensors
EP2664914A1 (en) * 2012-05-16 2013-11-20 Koninklijke Philips N.V. Magnetically assisted processing of a medium
CN104395751B (en) 2012-06-29 2016-10-19 皇家飞利浦有限公司 The process of the fluid containing interference granule
JP6309950B2 (en) 2012-07-18 2018-04-11 コーニンクレッカ フィリップス エヌ ヴェＫｏｎｉｎｋｌｉｊｋｅ Ｐｈｉｌｉｐｓ Ｎ．Ｖ． Processing sample fluids with target components
US9435800B2 (en) 2012-09-14 2016-09-06 International Business Machines Corporation Sample assembly with an electromagnetic field to accelerate the bonding of target antigens and nanoparticles
US10542918B2 (en) 2013-10-23 2020-01-28 Verily Life Sciences Llc Modulation of a response signal to distinguish between analyte and background signals
US10078148B2 (en) * 2013-11-26 2018-09-18 Minelab Electronics Pty Limited Metal detector
US9678137B2 (en) * 2014-02-26 2017-06-13 Dell Products L.P. System and method to monitor contact joint integrity
KR101705151B1 (en) * 2015-10-23 2017-02-13 한국표준과학연구원 Signal processing apparatus and method for controlling clock according to analog to digital conversion thereof
EP3290938A1 (en) 2016-09-05 2018-03-07 Industrial Technology Research Institute Biomolecule magnetic sensor
PT110107B (en) 2017-05-26 2021-11-16 Univ Aveiro PROBE ELEMENT AND METHODS FOR TEMPERATURE-CONTROLLED ANALYTE SEPARATION AND DETECTION
CN108627190B (en) * 2017-07-28 2023-12-19 杭州思泰微电子有限公司 High-precision magnetic sensor correction structure and correction method based on integrated circuit
CN114123977B (en) * 2021-11-26 2022-11-29 南京鼓楼医院 White noise generation method based on controllable fracture junction

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020060565A1 (en) * 1999-10-13 2002-05-23 Nve Corporation Magnetizable bead detector

Family Cites Families (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5981297A (en) * 1997-02-05 1999-11-09 The United States Of America As Represented By The Secretary Of The Navy Biosensor using magnetically-detected label
US6437563B1 (en) * 1997-11-21 2002-08-20 Quantum Design, Inc. Method and apparatus for making measurements of accumulations of magnetically susceptible particles combined with analytes
US6046585A (en) * 1997-11-21 2000-04-04 Quantum Design, Inc. Method and apparatus for making quantitative measurements of localized accumulations of target particles having magnetic particles bound thereto
JP3443007B2 (en) * 1998-08-03 2003-09-02 株式会社山武 Electromagnetic flow meter
JP4090722B2 (en) * 2001-10-23 2008-05-28 純一 小川 Magnetic fluid detection device
ATE326697T1 (en) * 2001-12-21 2006-06-15 Koninkl Philips Electronics Nv SENSOR AND METHOD FOR MEASURING THE AREA DENSITY OF MAGNETIC NANOPARTICLES ON A MICROARRAY
WO2003054566A1 (en) * 2001-12-21 2003-07-03 Koninklijke Philips Electronics N.V. Magnetoresistive sensing device, system and method for determining a density of magnetic particles in fluid
US6737862B1 (en) * 2003-05-14 2004-05-18 Delphi Technologies, Inc. Magnetosensitive latch engagement detector for a mechanical fastening system

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020060565A1 (en) * 1999-10-13 2002-05-23 Nve Corporation Magnetizable bead detector

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104969085A (en) * 2012-07-13 2015-10-07 蒙彼利埃大学 Micromagnetometry detection system and method for detecting magnetic signatures of magnetic materials.
CN104969085B (en) * 2012-07-13 2018-03-02 蒙彼利埃大学 For micro- the magnetometry detecting system and method for the magnetic characteristic for detecting magnetic material

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